Novel potential treatment options for infections caused by multi-drug and extensively drug-resistant Neisseria gonorrhoeae strains.
INTRODUCTION: Neisseria gonorrhoeae has evolved antimicrobial resistance (AMR) since antimicrobial treatment of gonorrhea was introduced. The AMR development is driven by the bacterium's high capacity for genetic adaptation, antimicrobial overuse and misuse, and insufficient surveillance. Novel therapeutic options are urgently needed. AREAS COVERED: This review summarizes novel gonorrhea treatment options, with special emphasis on the novel oral antimicrobials zoliflodacin and gepotidacin that obtained US FDA-approval for treatment of uncomplicated urogenital gonorrhea in December 2025. It also highlights compounds in early clinical or preclinical development that have demonstrated promising in vitro activity against N. gonorrhoeae. EXPERT OPINION: Zoliflodacin and gepotidacin have the potential to optimize gonorrhea management as oral alternatives to current injectable ceftriaxone. Their successful long-term use will depend on optimized use strategies, including indications, evidence-based approved dosing, adherence, surveillance, and population-specific considerations. Public-health agencies and clinicians will need to balance broad clinical access with antimicrobial stewardship measures to delay the AMR emergence. Looking ahead, gonorrhea management will hopefully shift from empirical, syndromic treatment toward etiology-guided and AMR-informed therapy, driven by advances in rapid point-of-care testing and whole-genome sequencing technologies. Continuous phenotypic and genomic surveillance remains essential to detect early AMR signals, transmission of AMR strains, and inform treatment guidelines.